The general objective is to elucidate the modes and mechanisms by which local factors influence the response of sympathetically innervated organs to adrenergic drugs and to nerve stimulation. Specific investigations will be concerned with the role of calcium ions and other ions in the release of norepinephrine from the adrenergic nerve terminals in response to nerve action potentials; the modulation of release of norepinephrine by acetylcholine, norepinephrine and other drugs acting on receptors on or near the nerve terminals; the unusual resistance to adrenergic blocking agents of nerve-evoked contraction of certain smooth muscle organs; the disposal and metabolism of nerve- released NE and administered adrenergic drugs in sympathetically innervated organs; application of concepts of receptor theory in the quantitative pharmacological characterization of adrenergic receptors; and the role of cyclic-AMP in the relaxation of smooth muscles produced by adrenergic agonists acting on beta receptors. Most experiments will be carried out on perfused organs and isolated organs and tissues, some with sympathetic nerves attached and available for stimulation. Physiological, pharmacological and biochemical approaches will be employed. Use will be made of radioactive labeled compounds, such as H3-NE, Ca 45 and P32-ATP, where appropriate.